Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication
Lin Lin,
Da-Yuan Chen,
Christina Scartelli,
Huanzhang Xie,
Glenn Merrill-Skoloff,
Moua Yang,
Lijun Sun,
Mohsan Saeed,
Robert Flaumenhaft
Affiliations
Lin Lin
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; College of Materials and Chemical Engineering, Minjiang University, Fuzhou Institute of Oceanography, Fuzhou, China
Da-Yuan Chen
National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, USA; Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
Christina Scartelli
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Huanzhang Xie
College of Materials and Chemical Engineering, Minjiang University, Fuzhou Institute of Oceanography, Fuzhou, China
Glenn Merrill-Skoloff
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Moua Yang
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Lijun Sun
Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Mohsan Saeed
National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, USA; Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
Robert Flaumenhaft
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Corresponding author
Summary: Plant-based flavonoids have been evaluated as inhibitors of β-coronavirus replication and as therapies for COVID-19 on the basis of their safety profile and widespread availability. The SARS-CoV-2 main protease (Mpro) has been implicated as a target for flavonoids in silico. Yet no comprehensive in vitro testing of flavonoid activity against SARS-CoV-2 Mpro has heretofore been performed. We screened 1,019 diverse flavonoids for their ability to inhibit SARS-CoV-2 Mpro. Multiple structure-activity relationships were identified among active compounds such as enrichment of galloylated flavonoids and biflavones, including multiple biflavone analogs of apigenin. In a cell-based SARS-CoV-2 replication assay, the most potent inhibitors were apigenin and the galloylated pinocembrin analog, pinocembrin 7-O-(3''-galloyl-4'',6''-(S)-hexahydroxydiphenoyl)-beta-D-glucose (PGHG). Molecular dynamic simulations predicted that PGHG occludes the S1 binding site via a galloyl group and induces a conformational change in Mpro. These studies will advance the development of plant-based flavonoids—including widely available natural products—to target β-coronaviruses.
